This invention relates to pharmaceutically useful compounds, in particular compounds which are useful in the inhibition of cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDEs), such as type 5 cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDE5). The compounds therefore have utility in a variety of therapeutic areas, including male erectile dysfunction (MED).
Certain cGMP PDE-inhibiting 2-phenyl substituted imidazotriazinone derivatives are disclosed in international patent application WO 99/24433.
According to a first aspect of the invention there is provided compounds of formula I, 
wherein
R1 and R2 independently represent phenyl (optionally substituted by one or more substituents selected from halo, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, C1-4 alkoxy or C1-4 alkyl (which latter two groups are optionally substituted by C1-4 haloalkyl or C1-4 haloalkoxy)) or C1-6 alkyl optionally interrupted by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and/or xe2x80x94N(R4)xe2x80x94 and/or optionally substituted and/or terminated by Het2, a N-linked heterocyclic group (selected from piperidinyl and morpholinyl) or phenyl (which latter group is optionally substituted by one or more substituents selected from halo, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, C1-4 alkoxy or C1-4 alkyl (which latter two groups are optionally substituted by C1-4 haloalkyl or C1-4 haloalkoxy));
R4 represents H or C1-4 alkyl;
R3 represents OR5 or N(R6)R7;
R5 represents C3-6 cycloalkyl, xe2x80x94(C1-4 alkylene)-1-piperidinyl, tetrahydrofuranyl, tetrahydropyranyl or C1-6 alkyl, which latter group is optionally substituted and/or terminated by one or two substituents selected from C3-5 cycloalkyl, xe2x80x94OR8, xe2x80x94N(R6)R7, phenyl, furanyl and pyridinyl, and which C1-6 alkyl group is optionally terminated by a C1-4 haloalkyl group;
R6 and R7 independently represent, at each occurrence when used herein, H, C1-4 alkyl (optionally substituted by C3-5 cycloalkyl or C1-4 alkoxy), or R6 and R7, together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl group;
R8 represents H, C1-4 alkyl (which C1-4 alkyl group is optionally terminated by a C1-4 haloalkyl group) or benzyl;
Het1 represents a 4-R9-1-piperazinyl group optionally substituted with one or two C1-4 alkyl groups and optionally in the form of its 4-N-oxide;
R9 represents H, pyridinyl, pyrimidinyl, C3-6 alkenyl or C1-4 alkyl optionally substituted by one or two substituents selected from xe2x80x94OH, xe2x80x94N(R6)R7, xe2x80x94C(O)N(R6)R7, benzodioxolyl, benzodioxanyl or phenyl (which latter group is optionally substituted by C1-4 alkoxy);
Het2 represents a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a C-linked 5-membered heterocyclic group containing two or three nitrogen atoms, wherein either of said heterocyclic groups is optionally substituted with C1-4 alkyl, C1-4 alkoxy or N(H)R10; and
R10 represents H, C1-4 alkyl or C1-4 alkanoyl;
or a pharmaceutically, or a veterinarily, acceptable derivative thereof;
which compounds are referred to together hereinafter as xe2x80x9cthe compounds of the inventionxe2x80x9d.
Unless otherwise indicated, each alkyl, alkoxy and alkenyl group identified herein may, when there is a sufficient number of carbon atoms (i.e. three) be linear or branched chain. Alkanoyl groups identified herein may also, when there is a sufficient number of carbon atoms (i.e. four) be linear or branched chain. The term xe2x80x9chaloxe2x80x9d, when used herein, includes fluoro, chloro, bromo and iodo. As used herein, haloalkyl and haloalkoxy groups are preferably xe2x80x94CF3 and xe2x80x94OCF3 respectively.
For the avoidance of doubt, each R6 and R7 group identified herein is independent of other R6 and R7 groups, respectively. For example, when R5 and R9 both represent alkyl substituted by xe2x80x94N(R6)R7, the two individual xe2x80x94N(R6)R7 substituents are independent of one another, and are not necessarily identical (though this possibility is not excluded).
The term xe2x80x9cpharmaceutically, or a veterinarily, acceptable derivativexe2x80x9d includes salts and solvates. The pharmaceutically or veterinarily acceptable salts of the compounds of the invention which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric and phosphoric acid, with carboxylic acids or with organo-sulphonic acids.
Examples include the HCl, HBr, HI, sulphate or bisulphate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccarate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts. Compounds of the invention can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts, with bases. Examples include the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts. Pharmaceutically acceptable derivatives also include C1-4 alkyl ammonium salts. For a review on suitable pharmaceutical salts see Berge et al, J. Pharm, Sci., 66, 1-19, 1977.
The pharmaceutically acceptable solvates of the compounds of the invention include the hydrates thereof.
Also included within the scope of the compound and various salts of the invention are polymorphs thereof.
Abbreviations are listed at the end of this specification.
Preferred compounds of the invention include those wherein:
R1 and R2 independently represent optionally substituted phenyl or C1-4 alkyl optionally substituted and/or terminated by Het2 or optionally substituted phenyl;
R3 represents OR5;
R5 represents C1-5 alkyl optionally substituted and/or terminated by C1-2 alkoxy;
Het1 represents a 4-R9-1-piperazinyl group;
R9 represents C1-4 alkyl;
Het2 represents an optionally substituted C-linked 6-membered heterocyclic group containing two, or preferably one, nitrogen atoms.
More preferred compounds of the invention include those wherein:
R1 and R2 independently represent phenyl, methyl, ethyl, propyl, benzyl or pyridylmethyl;
R3 represents ethoxy (optionally substituted or terminated by a methoxy group), propoxy or butoxy;
Het1 represents 4-ethyl-1-piperazinyl.
The compounds of the invention may exhibit tautomerism. All tautomeric forms of the compounds of formula I and mixtures thereof, are included within the scope of the invention.
A compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. Where a compound of the formula (I) contains an alkenyl or alkenylene group, cis (E) and trans (Z) isomerism may also occur. The present invention includes the individual stereoisomers of the compounds of the formula (I) and, where appropriate, the individual tautomeric forms thereof, together with mixtures thereof. Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
All stereoisomers are included within the scope of the invention.
Also included within the scope of the invention are radiolabelled derivatives of compounds of formula I which are suitable for biological studies.
Preparation
According to a further aspect of the invention there is provided processes for the preparation of compounds of the invention, as illustrated below.
The following processes are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention:
1. Compounds of formula I may be prepared by reaction of a corresponding compound of formula II, 
wherein L1 represents a suitable leaving group (e.g. halo), and R1, R2 and R3 are as hereinbefore defined, with a compound of formula III,
Het1xe2x80x94Hxe2x80x83xe2x80x83III
wherein Het1 is as hereinbefore defined, provided that the 1-N atom of the piperazine is attached to the H-atom.
This reaction is typically performed at between xe2x88x9210xc2x0 C. and room temperature in the presence of an appropriate solvent (e.g. a C1-3 alcohol, ethyl acetate or dichloromethane), an excess of the compound of formula III and, optionally, another suitable base (e.g. triethylamine or N-ethyidiisopropylamine).
Compounds of formula II may be prepared from a corresponding compound of formula IV, 
wherein R1, R2 and R3 are as hereinbefore defined, for example using methods known to those skilled in the art for converting an amino group to an SO2L1 group, in which L1 is as hereinbefore defined. For example, compounds of formula II in which L1 is chloro may be prepared by reacting a corresponding compound of formula IV, at between about xe2x88x9225 and about 0xc2x0 C., with about a 1.5 to 2-fold excess of sodium nitrite in a mixture of concentrated hydrochloric acid and glacial acetic acid, followed by treatment, at between xe2x88x9230xc2x0 C. and room temperature, with excess liquid sulfur dioxide and a solution of about a three-fold excess of cupric chloride in aqueous acetic acid.
Compounds of formula IV may be prepared by cyclisation of a corresponding compound of formula V, 
wherein R1, R2 and R3 are as hereinbefore defined, for example under conditions known to those skilled in the art. Such conditions include reaction, at between room and reflux temperature, in the presence of a suitable (Lewis acidic) dehydrating agent (e.g. phosphorous oxychloride) and an appropriate solvent (e.g. 1,2-dichloroethane), or as otherwise described in the prior art.
Compounds of formula V may be prepared by the reduction of a corresponding compound of formula VI, 
wherein R1, R2 and R3 are as hereinbefore defined, for example by conventional techniques, such as catalytic hydrogenation. Typically, the hydrogenation may be achieved at between 40 and 50xc2x0 C. using a Raney(copyright) nickel catalyst in a suitable solvent (e.g. ethanol) at a hydrogen pressure of between 150 kPa and 500 kPa.
Compounds of formula VI may be prepared by reaction of a corresponding compound of formula VII, 
wherein R11 represents lower (e.g. C1-6) alkyl, and R1 and R2 are as hereinbefore defined, with a compound of formula VIII, 
or a suitable acid addition salt thereof (e.g. an hydrogen chloride salt), wherein R3 is as hereinbefore defined, for example under conditions known to those skilled in the art. Such conditions include, for example, reaction at between room and reflux temperature (e.g. 70xc2x0 C.) in the presence of a suitable solvent (e.g. ethanol, ether, 1,4-dioxane or DMF).
Compounds of formula VII may be prepared via standard techniques, for example by decarboxylation of a corresponding compound of formula IX, 
wherein R1, R2 and R11 are as hereinbefore defined, for example under conditions known to those skilled in the art. Such conditions include, for example, reaction at elevated temperature (e.g. reflux temperature) in the presence of a suitable solvent (e.g. methanol or ethanol) and optionally in the presence of a suitable base (e.g. sodium hydrogencarbonate).
Compounds of formula IX may be prepared by reaction of a corresponding compound of formula X, 
wherein R1 and R2 are as hereinbefore defined, with a compound of formula XI, 
wherein R11 and L1 are as hereinbefore defined, for example under conditions known to those skilled in the art. Such conditions include reaction, at between room and reflux temperature, in the presence of a suitable organic solvent (e.g. THF or ether), an appropriate base (e.g. pyridine, sodium hydride, potassium tert-butoxide, lithium diisopropylamide, piperidine or triethylamine) and optionally in the presence of a suitable catalyst (e.g. 4-(dimethylamino)pyridine).
Compounds of formula VII may alternatively be prepared by reaction of a corresponding compound of formula XII, 
wherein R1, R2 and R11 are as hereinbefore defined, with ozone in a stream of oxygen, followed by reduction of the resulting ozonide, for example, for both steps, under conditions known to those skilled in the art. Conditions for the ozonation include, for example, reaction at sub-ambient temperature (e.g. xe2x88x9270xc2x0 C.) in the presence of a suitable solvent (e.g. dichloromethane). Conditions for reduction of the intermediate ozonide include, for example, reaction at sub-ambient temperature (e.g. xe2x88x9270xc2x0 C.) with a suitable reducing agent (e.g. dimethyl sulfide), followed by treatment (at the same temperature) with an appropriate base (e.g. pyridine).
Compounds of formula XII may be prepared by reaction of a corresponding compound of formula XIII, 
wherein L2 represents a suitable leaving group (e.g. xe2x80x94N(CH3)OCH3 or halo) and R1 and R2 are as hereinbefore defined, with a compound of formula XIV, 
wherein M represents H or a suitable metal-containing moiety (e.g. Na, Li, Mg(II) halide, or a cuprate) and R11 is as hereinbefore defined, for example under conditions known to those skilled in the art. Such conditions include, for example, reaction of a compound of formula XIII at between xe2x88x9280xc2x0 C. and room temperature in the presence of a suitable solvent (e.g. THF) with a mixture formed by reacting, at sub-ambient temperature (e.g. xe2x88x9278xc2x0 C.), a compound of formula XIV in which M represents H (e.g. ethyl vinyl ether), a suitable organolithium reagent (e.g. tert-butyllithium), an appropriate solvent (e.g. THF) and, optionally, a source of a suitable metal salt (e.g. MgBr2 diethyl etherate).
Compounds of formula XIII may be prepared from corresponding compounds of formula X, as hereinbefore defined, under conditions known to those skilled in the art.
Compounds of formula VIII may be prepared via standard techniques, for example by reaction of a corresponding compound of formula XV, 
or an acid addition salt thereof (e.g. a hydrogen chloride salt), wherein R3 is as hereinbefore defined, with hydrazine, for example under conditions known to those skilled in the art. Such conditions include, for example, reaction at between xe2x88x9210xc2x0 C. and room temperature in the presence of a suitable solvent (e.g. a lower alkyl (e.g. C1-3) alcohol), or as otherwise described in the prior art.
In a particular embodiment, a compound of formula VIII is formed in situ by reaction at low to ambient temperature (e.g. xe2x88x9210 to 25xc2x0 C.) of a compound of formula XV with hydrazine hydrate in an alcoholic solution. This is followed by addition of a compound of formula VII, after which the mixture is brought to reflux, eventually yielding a compound of formula VI.
Compounds of formula XV may be prepared from the corresponding cyanopyridine under conditions known to those skilled in the art.
Compounds of formula IV may alternatively be prepared by reduction of a corresponding compound of formula XVI, 
wherein R1, R2 and R3 are as hereinbefore defined, for example under reduction conditions known to those skilled in the art (e.g. as hereinbefore described for the synthesis of compounds of formula V).
Compounds of formula XVI may be prepared in an analogous manner to compounds of formula IV.
Compounds of formula II may alternatively be prepared from a corresponding compound of formula XVII, 
wherein R1, R2 and R3 are as hereinbefore defined, for example by reaction under conditions for conversion of a thiol to an xe2x80x94SO2L1 group that are known to those skilled in the art. For example, for compounds of formula II in which L1 represents halo, the reaction may be carried out at between xe2x88x9210xc2x0 C. and reflux temperature in the presence of a suitable oxidising agent (e.g. potassium nitrate), an appropriate halogenating agent (e.g. thionyl chloride) and a suitable solvent (e.g. acetonitrile).
Compounds of formula XVII may be prepared by reaction of a corresponding compound of formula XVIII, 
wherein R1, R2, R3 and L1 are as hereinbefore defined, with a suitable sulfur-delivering reagent. For example, the reaction may be carried out at between room and reflux temperature in the presence of thiourea, an appropriate coupling catalyst (e.g. dichlorobis(triethylphosphine)nickel(II) in combination with a reducing agent such as sodium cyanoborohydride) and a suitable solvent (e.g. N,N-dimethylformamide), followed by cleavage of the resulting thiopseudourea under hydrolytic conditions (e.g. by reaction with a base such as calcium oxide).
Compounds of formula XVIII may be prepared by cyclisation of a corresponding compound of formula XIX, 
wherein R1, R2, R3 and L1 are as hereinbefore defined, for example as hereinbefore described for the synthesis of compounds of formula IV.
Compounds of formula XIX may be prepared by reaction of a corresponding compound of formula XX, 
wherein R3 and L1 are as hereinbefore defined, with a compound of formula VII, as hereinbefore defined, for example under conditions described hereinbefore for the synthesis of compounds of formula VI.
2. Compounds of formula I may alternatively be prepared by cyclisation of a corresponding compound of formula XXI, 
wherein R1, R2, R3 and Het1 are as hereinbefore defined, for example as hereinbefore described for the synthesis of compounds of formula IV.
Compounds of formula XXI may be prepared by reaction of a corresponding compound of formula XXII, 
wherein R3 and Het1 are as hereinbefore defined, with a compound of formula VII, as hereinbefore defined, for example under conditions described hereinbefore for the synthesis of compounds of formula VI.
Compounds of formula XXI may alternatively be prepared by reaction of a corresponding compound of formula XXIII, 
wherein R1, R2, R3 and L1 are as hereinbefore defined, with a compound of formula III, as hereinbefore defined, for example under conditions described hereinbefore for the synthesis of compounds of formula I.
Compounds of formula I may alternatively be prepared in accordance, and/or by analogy, with methods described in the prior art for the synthesis of 2-substituted imidazotriazinone ring systems, for example as described in international patent application WO 99/24433 (the disclosure in which document is hereby incorporated by reference).
Compounds of formulae III, X, XI, XIV, XX, XXII, XXIII and derivatives thereof, when not commercially available or not subsequently described, may be obtained either by analogy with the processes described hereinbefore, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
Substituents on phenyl and Het (Het1, Het2) groups in the above-mentioned compounds may be introduced, removed and interconverted, using techniques which are well known to those skilled in the art. For example, compounds of formula I as described hereinbefore, in which either R1 or R2 represents C1-6 alkyl substituted by an alkylphenyl group, may be prepared by alkylation of a corresponding compound of formula I in which R1 or R2 represents C1-6 alkyl substituted by a phenyl group. The reaction may be performed using methods which are well known to those skilled in the art.
The skilled person will also appreciate that various standard substituent or functional group interconversions and transformations within certain compounds of formula I will provide other compounds of formula I. For example, for compounds of formula I in which R3 represents OR5, alkoxide exchange at the 2-position of the pyridin-3-yl substituent. Moreover, certain compounds of formula I for example those in which Het1 represents a 4-R9-1-piperazinyl group, in which R9 does not represent H, may be prepared directly from the corresponding piperazine analogues in which R9 represents H, using standard procedures (e.g. alkylation).
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the course of carrying out the processes described above, the functional groups of intermediate compounds may need to be protected by protecting groups.
Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butydimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and alkylcarbonyl groups (e.g. methyl- and ethylcarbonyl). Suitable protecting groups for amino include tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C1-6 alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by JWF McOmie, Plenum Press (1973), and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, T W Greene and P G M Wutz, Wiley-Interscience (1991).
Persons skilled in the art will also appreciate that, in order to obtain compounds of formula I in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis.
Pharmaceutically acceptable acid addition salts of the compounds of formula I that contain a basic centre may be prepared in a conventional manner. For example, a solution of the free base may be treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt may then be isolated either by filtration or by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula I with the appropriate base. Both types of salt may be formed or interconverted using ion-exchange resin techniques.
The present invention also includes all suitable isotopic variations of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. An isotopic variation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the formula (I) and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F and 36Cl, respectively. Certain isotopic variations of the compounds of the formula (I) and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of formula (I) and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Preparations hereafter using appropriate isotopic variations of suitable reagents.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula I which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Further, certain compounds of formula I may act as prodrugs of other compounds of formula I.
All protected derivatives, and prodrugs, of compounds of formula I are included within the scope of the invention.
Medical Use
The compounds of the invention are useful because they possess pharmacological activity in animals, especially mammals, including humans. They are therefore indicated as pharmaceuticals, as well as for use as animal medicaments.
According to a further aspect of the invention there is provided the compounds of the invention for use as pharmaceuticals, and for use as animal medicaments.
In particular, compounds of the invention have been found to be potent and selective inhibitors of cGMP PDEs, such as cGMP PDE5, for example as demonstrated in the tests described below, and are thus useful in the treatment of medical conditions in humans, and in animals, in which cGMP PDEs, such as cGMP PDE5, are indicated, and in which inhibition of cGMP PDEs, such as cGMP PDE5, is desirable.
By the term xe2x80x9ctreatmentxe2x80x9d, we include both therapeutic (curative), palliative or prophylactic treatment.
Thus, according to a further aspect of the invention there is provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a medical condition in which a cGMP PDE (e.g. cGMP PDE5) is indicated. There is further provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a medical condition in which inhibition of a cGMP PDE (e.g. cGMP PDE5) is desirable or required.
The compounds of the invention are thus expected to be useful for the curative, palliative or prophylactic treatment of mammalian sexual disorders. In particular, the compounds are of value in the treatment of mammalian sexual dysfunctions such as male erectile dysfunction (MED), impotence, female sexual dysfunction (FSD), clitoral dysfunction, female hypoactive sexual desire disorder, female sexual arousal disorder, female sexual pain disorder or female sexual orgasmic dysfunction (FSOD) as well as sexual dysfunction due to spinal cord injury but, clearly, will be useful also for treating other medical conditions for which a potent and selective cGMP PDE5 inhibitor is indicated. Such conditions include premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, coronary artery disease, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, nitrate induced tolerance, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).
Further medical conditions for which a potent and selective cGMP PDE5 inhibitor is indicated, and for which treatment with compounds of the present invention may be useful include pre-eclampsia, Kawasaki""s syndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy, peripheral diabetic neuropathy, Alzheimer""s disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, nutcracker oesophagus, anal fissure, haemorrhoids and hypoxic vasoconstriction.
Particularly preferred conditions include MED and FSD.
Thus the invention provides a method of treating or preventing a medical condition for which a cGMP PDE5 inhibitor is indicated, in an animal (e.g. a mammal, including a human being), which comprises administering a therapeutically effective amount of a compound of the invention to a mammal in need of such treatment.
Pharmaceutical Preparations
The compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses.
The compounds of the invention may also be combined with any other drugs useful in the inhibition of cGMP-PDEs, such as cGMP-PDE5.
The compounds of the invention, their pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of either entity can be administered alone but, in human therapy will generally be administered in admixture with a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compounds of the invention or salts or solvates thereof can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, controlled-release or pulsatile delivery applications. The compounds of the invention may also be administered via intracavernosal injection. The compounds of the invention may also be administered via fast dispersing or fast dissolving dosages forms.
Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
Modified release and pulsatile release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/or included in the body of the device. Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof. Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients. Release rate modifying excipients maybe present both within the dosage form i.e. within the matrix, and/or on the dosage form i.e. upon the surface or coating.
Fast dispersing or dissolving dosage formulations (FDDFS) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol.
The compounds of the invention can also be administered parenterally, for example, intracavernosally, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. For such parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of the compounds of the invention or salts or solvates thereof will usually be from 10 to 500 mg (in single or divided doses).
Thus, for example, tablets or capsules of the compounds of the invention or salts or solvates thereof may contain from 5 mg to 250 mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention. The skilled person will also appreciate that, in the treatment of certain conditions (including MED and FSD), compounds of the invention may be taken as a single dose on an xe2x80x9cas requiredxe2x80x9d basis (i.e. as needed or desired).
Example Tablet Formulation
In general a tablet formulation could typically contain between about 0.01 mg and 500 mg of a compound according to the present invention (or a salt thereof) whilst tablet fill weights may range from 50 mg to 1000 mg. An example formulation for a 10 mg tablet is illustrated:
The compounds of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A(trademark) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA(trademark)), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d contains from 1 to 50 mg of a compound of the invention for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 1 to 50 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
The compounds of the invention may also be formulated for delivery via an atomiser. Formulations for atomiser devices may contain the following ingredients as solubilisers, emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid.
Alternatively, the compounds of the invention or salts or solvates thereof can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the invention or salts or solvates thereof may also be dermally administered. The compounds of the invention or salts or solvates thereof may also be transdermally administered, for example, by the use of a skin patch. They may also be administered by the ocular, pulmonary or rectal routes.
For ophthalmic use, the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
For application topically to the skin, the compounds of the invention or salts or solvates thereof can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the invention may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
Generally, in humans, oral administration of the compounds of the invention is the preferred route, being the most convenient and, for example in MED, avoiding the well-known disadvantages associated with intracavernosal (i.c.) administration. A preferred oral dosing regimen in MED for a typical man is from 25 to 250 mg of compound when required. In circumstances where the recipient suffers from a swallowing disorder or from impairment of drug absorption after oral administration, the drug may be administered parenterally, sublingually or buccally.
For veterinary use, a compound of the invention, or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate or pro-drug thereof, is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
Thus, according to a further aspect of the invention there is provided a pharmaceutical formulation including a compound of the invention in admixture with a pharmaceutically or veterinarily acceptable adjuvant, diluent or carrier.
In addition to the fact that compounds of the invention inhibit cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDEs) and in particular, are potent and selective inhibitors of cGMP PDE5, compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, be more easily absorbed than, or they may have other useful pharmacological properties over, compounds known in the prior art.
The present invention additionally comprises the combination of a cGMP PDE5 inhibitor, in particular a compound of the general formula (I) with:
(a) one or more naturally occurring or synthetic prostaglandins or esters thereof. Suitable prostaglandins for use herein include compounds such as alprostadil, prostaglandin E1,prostaglandin E0, 13, 14-dihydroprosta glandin E1, prostaglandin E2, eprostinol, natural synthetic and semi-synthetic prostaglandins and derivatives thereof including those described in U.S. Pat. No. 6,037,346 issued on Mar. 14, 2000 and incorporated herein by reference, PGE0, PGE1, PGA1, PGB1, PGF1 xcex1, 19-hydroxy PGA1, 19-hydroxy-PGB1, PGE2, PGB2, 19-hydroxy-PGA2, 19-hydroxy-PGB2, PGE3xcex1, carboprost tromethamine dinoprost, tromethamine, dinoprostone, lipo prost, gemeprost, metenoprost, sulprostune, tiaprost and moxisylate; and/or
(b) one or more xcex1-adrenergic receptor antagonist compounds also known as xcex1-adrenoceptors or xcex1-receptors or xcex1-blockers. Suitable compounds for use herein include: the xcex1-adrenergic receptors as described in PCT application WO99/30697 published on Jun. 14, 1998, the disclosures of which relating to xcex1-adrenergic receptors are incorporated herein by reference and include, selective xcex11-adrenoceptors or xcex12-adrenoceptors and non-selective adrenoceptors, suitable xcex11-adrenoceptors include: phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramin, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaraxan, yohimbine, rauwolfa alkaloids, Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591, doxazosin, terazosin, abanoquil and prazosin; xcex12-blockers from U.S. Pat. No. 6,037,346 [Mar. 14, 2000] dibenarnine, tolazoline, trimazosin and dibenarnine; xcex1-adrenergic receptors as described in U.S. Pat. Nos. 4,188,390; 4,026,894; 3,511,836; 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252,721 and 2,599,000 each of which is incorporated herein by reference; xcex12-Adrenoceptors include: clonidine, papaverine, papaverine hydrochloride, optionally in the presence of a cariotonic agent such as pirxamine; and/or
(c) one or more NO-donor (NO-agonist) compounds. Suitable NO-donor compounds for use herein include organic nitrates, such as mono-di or tri-nitrates or organic nitrate esters including glyceryl brinitrate (also known as nitroglycerin), isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside (SNP),
3-morpholinosydnonimine molsidomine, S-nitroso-N-acetyl penicilliamine (SNAP) S-nitroso-N-glutathione (SNO-GLU), N-hydroxy-L-arginine, amylnitrate, linsidomine, linsidomine chlorohydrate, (SIN-1) S-nitroso-N-cysteine, diazenium diolates,(NONOates), 1,5-pentanedinitrate, L-arginene, ginseng, zizphi fructus, molsidomine, Re-2047, nitrosylated maxisylyte derivatives such as NMI-678-11 and NMI-937 as described in published PCT application WO 0012075; and/or
(d) one or more potassium channel openers. Suitable potassium channel openers for use herein include nicorandil, cromokalim, levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil, charybdotoxin, glyburide, 4-amini pyridine, BaCl2; and/or
(e) one or more dopaminergic agents. Suitable dopaminergic compounds for use herein include D2-agonists such as, pramipexol; apomorphine; and/or
(f) one or more vasodilator agents. Suitable vasodilator agents for use herein include nimodepine, pinacidil, cyclandelate, isoxsuprine, chloroprumazine, halo peridol, Rec 15/2739, trazodone, pentoxifylline; and/or
(g) one or more thromboxane A2 agonists; and/or
(h) one or more CNS active agents; and/or
(i) one or more ergot alkoloids; Suitable ergot alkaloids are described in U.S. Pat. No. 6,037,346 issued on Mar, 14, 2000 and include acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride, terguride; and/or
(k) one or more compounds which modulate the action of atrial natruretic factor (also known as atrial naturetic peptide), such as inhibitors or neutral endopeptidase; and/or
(l) one or more compounds which inhibit angiotensin-converting enzyme such as enapril, and combined inhibitors of angiotensin-converting enzyme and neutral endopeptidase such as omapatrilat; and/or
(m)one or more angiotensin receptor antagonists such as losartan; and/or
(n) one or more substrates for NO-synthase, such as L-arginine; and/or
(o) one or more calcium channel blockers such as amlodipine; and/or
(p) one or more antagonists of endothelin receptors and inhibitors or endothelin-converting enzyme; and/or
(q) one or more cholesterol lowering agents such as statins and fibrates; and/or
(r) one or more antiplatelet and antithrombotic agents, e.g. tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin activating factor inhibitors; and/or
(s) one or more insulin sensitising agents such as rezulin and hypoglycaemic agents such as glipizide; and/or
(t) L-DOPA or carbidopa; and/or
(u) one or more acetylcholinesterase inhibitors such as donezipil; and/or
(v) one or more steroidal or non-steroidal anti-inflammatory agents.
The biological activities of the compounds of the present invention may be determined by the following test methods.
Biological Tests
Phosphodiesterase (PDE) Inhibitory Activity In vitro PDE inhibitory activities against cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate (cGMP) and cyclic adenosine 3xe2x80x2,5xe2x80x2-monophosphate (cAMP) phosphodiesterases are determined by measurement of their IC50 values (the concentration of compound required for 50% inhibition of enzyme activity).
The required PDE enzymes were isolated from a variety of sources, including human corpus cavernosum, human and rabbit platelets, human cardiac ventricle, human skeletal muscle and bovine retina, essentially by the method of W. J. Thompson and M. M. Appleman (Biochem., 1971, 10, 311). In particular, the cGMP-specific PDE (PDE5) and the cGMP-inhibited cAMP PDE (PDE3) were obtained from human corpus cavernosum tissue, human platelets or rabbit platelets; the cGMP-stimulated PDE (PDE2) was obtained from human corpus cavernosum; the calcium/calmodulin (Ca/CAM)-dependent PDE (PDE1) from human cardiac ventricle; the cAMP-specific PDE (PDE4) from human skeletal muscle; and the photoreceptor PDE (PDE6) from bovine retina. Phosphodiesterases 7-11 were generated from full length human recombinant clones transfected into SF9 cells.
Assays were performed either using a modification of the xe2x80x9cbatchxe2x80x9d method of W. J. Thompson et al. (Biochem., 1979, 18, 5228) or using a scintillation proximity assay for the direct detection of AMP/GMP using a modification of the protocol described by Amersham plc under product code TRKQ7090/7100. In summary, the effect of PDE inhibitors was investigated by assaying a fixed amount of enzyme in the presence of varying inhibitor concentrations and low substrate, (cGMP or cAMP in a 3:1 ratio unlabelled to [3H]-labeled at a conc xcx9c1/3 Km) such that IC50xe2x89xa1Ki. The final assay volume was made up to 100 xcexcl with assay buffer [20 mM Tris-HCl pH 7.4, 5 mM MgCl2, 1 mg/ml bovine serum albumin]. Reactions were initiated with enzyme, incubated for 30-60 min at 30xc2x0 C. to give  less than 30% substrate turnover and terminated with 50 xcexcl yttrium silicate SPA beads (containing 3 mM of the respective unlabelled cyclic nucleotide for PDEs 9 and 11). Plates were re-sealed and shaken for 20 min, after which the beads were allowed to settle for 30 min in the dark and then counted on a TopCount plate reader (Packard, Meriden, Conn.) Radioactivity units were converted to % activity of an uninhibited control (100%), plotted against inhibitor concentration and inhibitor IC50 values obtained using the xe2x80x98Fit Curvexe2x80x99 Microsoft Excel extension. Results from these tests show that the compounds of the present invention are potent and selective inhibitors of cGMP-specific PDE5.
Functional Activity
This was assessed in vitro by determining the capacity of a compound of the invention to enhance sodium nitroprusside-induced relaxation of pre-contracted rabbit corpus cavernosum tissue strips, as described by S. A. Ballard et al. (Brit. J. Pharmacol., 1996, 118(suppl.), abstract 153P).
In vivo Activity
Compounds were screened in anaesthetised dogs to determine their capacity, after i.v. administration, to enhance the pressure rises in the corpora cavernosa of the penis induced by intracavernosal injection of sodium nitroprusside, using a method based on that described by Trigo-Rocha et al. (Neurourol. and Urodyn., 1994, 13, 71).
Safety Profile
Compounds of the invention may be tested at varying i.v and p.o. doses in animals such as mouse and dog, observing for any untoward effects.